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. 2025 Feb 25;44(2):115295.
doi: 10.1016/j.celrep.2025.115295. Epub 2025 Feb 12.

Mechanistic insight into the induction of liver tissue-resident memory CD8+ T cells by glycolipid-peptide vaccination

Yu Cheng Chua  1 , Sarah L Draper  2 , Shirley Le  1 , Maria N de Menezes  1 , Mitch Ganley  1 , Zhengyu Ge  1 , Ariane Lee  1 , Taylah Phabmixay  1 , Daria Hirschmann  1 , Sage A Robinson  3 , Peck Szee Tan  4 , Kirsteen M Tullett  4 , Regan J Anderson  2 , Dhilshan Jayasinghe  5 , Anton Cozijnsen  6 , Mireille H Lahoud  4 , Irina Caminschi  7 , Lynette Beattie  1 , Geoffrey I McFadden  6 , David S Larsen  3 , Tsuneyasu Kaisho  8 , Stephanie Gras  9 , Ian F Hermans  10 , Benjamin J Compton  2 , William R Heath  1 , Gavin F Painter  2 , Lauren E Holz  11
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Free article

Mechanistic insight into the induction of liver tissue-resident memory CD8+ T cells by glycolipid-peptide vaccination

Yu Cheng Chua et al. Cell Rep. .
Free article

Abstract

We recently demonstrated that vaccines comprising antigenic peptides conjugated to a glycolipid agonist, termed glycolipid-peptide (GLP) vaccines, efficiently generate substantial numbers of long-lived CD8+ liver-resident memory T (Trm) cells that are crucial for protection against malaria liver-stage infection. To understand the underlying mechanism, we examined the prerequisites for priming, differentiation, and secondary boosting of liver Trm cells using these GLP vaccines. Our study revealed that generation of long-lived liver Trm cells relies on CD8+ T cell priming by type 1 conventional dendritic (cDC1) cells, followed by post-priming exposure to a combination of vaccine-derived inflammatory and antigenic signals. Boosting of liver Trm cells is feasible using the same GLP vaccine, but a substantial delay is required for optimal responses due to natural killer T (NKT) cell anergy. Overall, our study unveils key requirements for the development of long-lived liver Trm cells, offering valuable insights for future vaccine design.

Keywords: CP: Immunology; glycolipid peptide; liver; tissue-resident memory T cells; vaccine.

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Conflict of interest statement

Declaration of interests G.F.P. and I.F.H. have been chief technical officer and chief scientific officer, respectively, of biotech start-up Avalia Immunotherapies Limited, and W.R.H. was a member of its Scientific Advisory Board. Avalia holds exclusive, worldwide license to patents related to aspects of the chemical design reported here. Avalia partially funded the study. W.R.H., I.F.H., L.E.H., B.J.C., and G.F.P. are inventors on patent application (WO2020231274) submitted by Victoria University of Wellington, Malcorp Biodiscoveries Limited, and Victoria Link Limited that covers the production of tissue-resident memory T cells with GLP vaccines. M.H.L., K.M.T., and I.C. are inventors on patents relating to Clec9A antibodies.